Epstein-Barr virus and immune chaos: the link between reactivation and Toll-like receptor dysregulation in immunodeficiency.

Background:  The immune system protects the body against pathogens, and its dysfunction leads to primary and secondary immunodeficiencies, increasing infection susceptibility. Epstein-Barr virus (EBV) reactivation is linked to immune homeostasis disorders, particularly in common variable immunodeficiency (CVID) and chronic lymphocytic leukemia (CLL). Toll‑like receptor (TLR) pathways play a crucial role in innate immunity, and their deregulation may contribute to immune dysfunction.

Objective:  This study aimed to assess the impact of EBV reactivation on immune homeostasis, focusing on TLR2, TLR4, TLR7, and TLR9 expression in T and B lymphocyte subpopulations and their soluble forms in CVID and CLL patients.

Methods:  The study included 60 CVID patients, 60 CLL patients, and 30 healthy controls. EBV antigens, viral DNA levels, T and B lymphocyte immunophenotypes, and serum soluble TLR (sTLR) concentrations were analyzed using flow cytometry and enzyme‑linked immunosorbent assay.

Results:  EBV reactivation was detected in 55% of CVID and 60% of CLL patients. These patients showed significant TLR expression disturbances and increased sTLR levels. Notably, TLR7 and TLR9 expression was elevated in CD4+, CD8+ T, and CD19+ B cells, correlating with EBV load and immune dysfunction severity.

Conclusions:  EBV reactivation plays a key role in TLR pathway deregulation in CVID and CLL, potentially accelerating disease progression and increasing infection risk. TLR expression and sTLR levels could serve as biomarkers for EBV reactivation, aiding therapeutic strategies to stabilize immune responses.